Hepatocellular carcinoma (HCC), the most common type of adult liver cancer, is the third leading cause of cancer deaths worldwide (Block T M et al. (2003), Oncogene 22, pp. 5093-5107). Many patients with HCC remain asymptomatic until the disease is in its advanced stages, resulting in ineffective treatment and poor prognosis; the majority of unresectable HCC patients die within one year. The clinical management of HCC can be expected to improve dramatically with improved screening tools to detect the carcinoma in the early stage.
The major risk factors of HCC are chronic infections with hepatitis B or hepatitis C virus (HBV or HCV, respectively). Chronic hepatitis can progress into cirrhosis (a noncancerous liver disease associated with fibrosis and abnormal nodules), which increases the risk of developing HCC. Patients with chronic hepatitis and/or cirrhosis, therefore, form a high risk population which would benefit from regular screening for HCC. Current screening tests for HCC are the measurement of alpha-fetoprotein (AFP) levels in the blood serum and the conduction of a hepatic ultrasound. Elevated serum AFP is, however, not a specific marker for HCC, since it is detected in a wide variety of non-hepatic malignancies and benign conditions, including acute and chronic hepatitis (McIntire KR et al. (1975), Cancer Res. 35, pp. 991-996; Liaw Y F (1986), Liver 6, pp. 133-137). Furthermore, 30-50% of HCC cases do not present with elevated serum AFP {Johnson P J (2001), Clin. Liver Dis. 5, pp. 145-159}. As a consequence, the AFP test can miss 50% of the positives due to its lack of sensitivity and specificity. A majority of HCC patients concomitantly suffers from cirrhosis. In those patients, the use of advanced imaging technology such as hepatic ultrasound is difficult and frequently non-conclusive.
Reliable non-invasive screening methods with improved sensitivity and specificity are critical and urgently needed for the accurate detection of HCC, particularly in high-risk subjects who exhibit symptoms of cirrhosis in the presence or absence of chronic hepatitis.